The primary purpose of the proposed study is the relationship between folic acid and vitamin B12. The specific objectives are: 1) To study the mechanism whereby thyroxine changes folic acid and vitamin B12 metabolism. Thyroxine has been found to increase vitamin B12 requirement and impair folic acid metabolism in both humans and animals. The effect of thyroidectomy and thyroxine on various vitamin B12- and folate-dependent enzymes will be studied. 2) To study purified preparations of the two enzymes: the ATP-dependent folate polyglutamate synthetase and the ATP-independent folate polyglutamate synthetase. 3) To isolate and determine the structure of x-methyl-folic acid and to prepare the corresponding 4-amino derivative of x-methyl-folic acid. These two compounds will be tested for their abilities to inhibit various folate-dependent enzymes and for their anti-tumor activities.